Atrial fibrillation (AF) remains the most common heart rhythm disturbance and the prevalence continues to grow exponentially. It is currently estimated that 33.5 million people worldwide are afflicted with AF. Once established, AF is associated with significant morbidity and mortality, much of which is not impacted by current treatment options. In this competing continuation of the VITAL Rhythm Study, we propose to continue our evaluation of the balance of benefits and risks of marine omega-3 fatty acid (840 mg eicosapentaenoic acid [EPA] + docosahexaenoic acid [DHA]) and vitamin D3 (2,000 IU/day cholecalciferol) on AF incidence in the setting of an NIH-funded large-scale clinical trial, the VITamin D and OmegA-3 TriaL (VITAL). VITAL is an ongoing, randomized, double-blind, placebo-controlled, 2x2 factorial trial specifically designed to evaluate the efficacy of vitamin D3 and marine omega-3 fatty acid supplements in the primary prevention of cancer and cardiovascular disease among 25,874 men (aged 50+ years) and women (aged 55+ years). Benefits and risks with respect to incident AF have been postulated for both of these commonly used supplements based on results from observational studies and short-term secondary prevention randomized trials, but definitive data from a large-scale primary prevention randomized trial are lacking. In this competing continuation, we propose to continue our ancillary study that is in the process of ascertaining and adjudicating AF outcomes within the VITAL trial to test whether long-term treatment (5-years) with omega-3 fatty acid and/or vitamin D3 supplementation has an impact on the incidence AF over 7-years of follow-up in an older population. Case validation of incident AF is ongoing and involves systematic ascertainment of physician diagnoses of AF on annual study questionnaires supplemented by CMS linkage followed by collection of detailed diagnostic information from medical records. The extended follow-up will allow us to fully ascertain and adjudicate the AF endpoints occurring throughout the 5 year VITAL randomized trial and a 2-year post-intervention period and determine whether these agents might have a selective impact on persistent versus paroxysmal forms of AF. Since both agents are known to impact biologic processes involved in atrial structural and electrical remodeling, long-term post-intervention benefits and/or selective benefits on persistent forms of AF are plausible. The additional endpoints that will be adjudicated during the continuation along with the separately funded measurements of plasma 25(OH)D and EPA+DHA assays in the VITAL trial will also allow us to perform important sub-analyses according to sex and baseline nutrient level. In summary, we propose to build on the infrastructure and processes created in the first funding cycle and continue to take advantage of the enormous investment of resources and infrastructure in the VITAL trial to provide a definitive and full assessment of the benefits and risks of these agents on AF incidence and persistence. If beneficial, then these agents would represent the first therapy proven effective for AF prevention.